Synthesis of the alkaloid homaline in (±) and natural (S,S)-(–) forms, using amination and transamidative ring expansion in liquid ammonia

Crombie, Leslie; Haigh, David; Jones, Raymond C. F.; Mat-Zin, Ab. Rasid

doi:10.1039/p19930002047

Cited by 28 publications

(20 citation statements)

References 15 publications

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“…In fact, due to the presence of anomalous scattering in the compound, e.g., of the S-atom, it was possible to independently determine the absolute configuration by Xray-diffraction analysis. Refinement of the absolute structure parameter [17] yielded a value of 0.05 (6), which confidently confirms that the refined coordinates represent the true enantiomorph.…”

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confidence: 57%

“…They are based biogenetically on a combination of two a,b-unsaturated carboxylic acid residues (fatty or cinnamic acid) with spermine (5). The best-defined member of the Homalium family is the major alkaloid homaline (1), the structure and absolute (S,S)-configuration of which have been confirmed by Xray single-crystal analysis [4] and manifold diastereoselective total synthesis [5] [6]. The configuration of the remaining three alkaloids 2 ± 4 is yet to be determined since the few reported preparations of these unsymmetrically substituted alkaloids are nonstereospecific [7].…”

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confidence: 99%

“…Bridging of both lactam units 21b and 21c by the C 4 chain was accomplished iteratively [6] [18]: first 21b was mono-alkylated with 1,4-dibromobutane under the action of powdered KOH in dry DMSO at room temperature overnight, then the resulting bromo derivative 22 was attached to 21c by adding a mixture of both to a frozen suspension of KOH in dry DMSO at 08 and slowly defreezing the solid reaction mixture overnight (Scheme 5). This treatment gave the bis-8-membered core 23 in 71% yield.…”

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confidence: 99%

“…Treatment of 13a analogous to that of 13b,c, i.e., N-alkylation followed by Boc-deprotection and Sb(OEt) 3 -assisted ring closure (Scheme 4), led to the cyclic lactam 21a in good yields. The symmetric, bis-8-membered scaffold 25 was built up by double alkylation of 1,4-dibromobutane with 21a and powdered KOH in dry DMSO [6] [18] (Scheme 6) under conditions comparable to those employed for the iterative linking of 21b with 21c. Electrolytic detosylation of 25 similarly to that of 23 and reductive methylation of didemethylhomaline 26 as described for 24 completed the total synthesis of (AE)-homaline (1).…”

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confidence: 99%

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Total Syntheses of the Spermine Alkaloids (−)-(R,R)-Hopromine and (±)-Homaline

Ensch

Hesse

2002

HCA

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The diastereoselective synthesis of the spermine alkaloid (R,R)-hopromine (2) is described. The as yet unknown absolute configuration of naturally occurring (À)-hopromine (2) is (R,R) and was established by comparison of the reported specific rotation of the natural product with that of the synthetic one. Preparation of the characteristic bis-8-membered lactam scaffold was carried out by convergent build-up of basic chiral azalactam units 21a and 21b and subsequent iterative linking (Schemes 5 and 6). Key steps in the analogous syntheses of 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 21a and 21b were the introduction of the unbranched alkyl side chains into their common precursor 14 via cuprate reaction and the Sb(OEt) 3 -assisted cyclization of the open-chain intermediates 20a and 20b, respectively (Schemes 3 and 4). The chiral iodoester 14 was prepared from commercially available ()-l-aspartic acid (12). Based on the synthetic strategy developed for (R,R)-hopromine (2), a rapid access to the parent alkaloid homaline (1) in its (AE)-form is given.

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confidence: 57%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Total Syntheses of the Spermine Alkaloids (−)-(R,R)-Hopromine and (±)-Homaline

Ensch

Hesse

2002

HCA

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“…The bridging of the two structural elements 7a and 7b by a C 4 chain was attempted iteratively [6] [17] (Scheme 5). In a first step, 7a was mono-alkylated with 1,4-dibromobutane to the bromo derivative 30 under the action of powdered KOH in dry DMSO at room temperature overnight.…”

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Enantioselective Entry to the Homalium Alkaloid Hoprominol: Synthesis of an (R,R,R)‐Hoprominol Derivative

Ensch¹,

Hesse²

2003

Helvetica Chimica Acta

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The diastereoselective synthesis of the N-and O-protected hoprominol derivative (R,R,R)-6 is described. The building up of the bicyclic O-silylated and di(N-tosylated) asymmetric scaffold 6 succeeded by convergent preparation of the two basic chiral azalactam units 7a and 7b and their subsequent iterative linking by a known method (Scheme 5). Both 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 7a and 7b were prepared from the chiral b-amino acid portions 10a and 10b, respectively, by application of a set of reactions (e.g., N-alkylation of 10a,b and Sb(OEt) 3 -assisted cyclization of the resulting open-chain intermediates) already known. In comparison with the total syntheses of homaline (1) and homoprine (2), the newness of the described synthesis lies in the asymmetric approach to the difunctionalized fatty acid derivative 10b starting from (À)-(S)-malic acid (9) (Schemes 3 and 4). Key step in the preparation of 10b was the diastereoselective amination of the optically pure a,b-unsaturated d-hydroxy homoallylic ester 14 via conjugate intramolecular aza-Michael cyclization of the acylic d-(carbamoyloxy) intermediate 11.Introduction. ± Isolated from the leaves of the New Caledonian plant Homalium pronyense Guillaum. (Flacourtiaceae) [2], the four Homalium alkaloids homaline (1), hopromine (2), hoprominol (3), and hopromalinol (4) constitute a small family of optically active natural products characterized by a unique bis-eight-membered lactam structure incorporating a spermine (5) backbone (Fig.). The structures of the Homalium alkaloids were elucidated in the seventies by Pais and co-workers [3], and the correctness of the proposed formulae was confirmed by several total syntheses since then.A single-crystal X-ray analysis [4] as well as manifold asymmetric syntheses [5] [6] allowed the determination of the absolute (S,S)-configuration of the major alkaloid homaline (1). In a preceding paper [1], we presented a new, potent synthetic entry to the Homalium scaffold that enabled us to prepare (AE)-homaline (1) and (À)-hopromine (2) and, hence, to determine the absolute configuration of the natural hopromine (2) as being (R,R). Since, hitherto, all the syntheses of the remaining, unsymmetrically substituted parent molecules hoprominol (3) and hopromalinol (4) are nonstereospecific [7], the absolute configurations of the alkaloids 3 and 4 are still unknown. Hereafter, we now wish to report the application of our previously described synthetic strategy for building up the bicyclic Homalium core by the preparation of the N-and O-protected (R,R,R)-hoprominol precursor 6 (Fig.), with the higher aim of elucidating the yet-undefined configuration of the natural product (À)-homprominol (3).

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